British journal of clinical pharmacology最新文献

{"title":"Development of a population pharmacokinetic model using combined paediatric and adult data for four pulmonary arterial hypertension drugs.","authors":"Motoyasu Miura, Shimako Tanaka, Ririka Aihara, Shun Yamamoto, Yasumi Nakashima, Yasuharu Kashiwagura, Akio Hakamata, Sachiko Miyakawa, Mariko Tatsuguchi, Keiichi Odagiri, Noriyuki Namiki, Naoki Inui, Hiroshi Watanabe, Shinya Uchida","doi":"10.1002/bcp.70676","DOIUrl":"10.1002/bcp.70676","url":null,"abstract":"<p><strong>Aims: </strong>Pulmonary arterial hypertension (PAH) is a syndrome characterized by elevated pulmonary artery pressure. We developed a population pharmacokinetic (PPK) model using combined plasma drug concentration data from Japanese paediatric (<15 years) and adult (≥15 years) patients with PAH to investigate the pharmacokinetic characteristics of PAH treatments (sildenafil, tadalafil, bosentan and ambrisentan).</p><p><strong>Methods: </strong>PPK analysis was conducted using a nonlinear mixed-effects modelling approach. A one-compartment model was selected as the structural model, and an exponential error model was used to describe interindividual variability. Individual patient clearance (CL), adjusted for bioavailability (F) using Bayesian estimation based on the PPK model, was used to estimate the steady-state plasma concentrations (C_ss) of the drugs in paediatric and adult patients receiving clinical dosages.</p><p><strong>Results: </strong>PPK analysis was performed on data from 35 paediatric and 16 adult subjects to estimate pharmacokinetic parameters. The population mean CL/F values for sildenafil, tadalafil, bosentan and ambrisentan were estimated at 60.6, 1.76, 8.85 and 0.594 L/h, respectively. Covariates that improved model performance and were incorporated into the final model included the effect of bodyweight on the CL/F of each drug. The estimated C_ss values for all drugs were 26.0%-72.2% lower in paediatric than in adult patients.</p><p><strong>Conclusions: </strong>This study clarified the pharmacokinetic parameters and their variability for sildenafil, tadalafil, bosentan and ambrisentan using combined data from Japanese paediatric and adult patients with PAH. The results of Bayesian estimation suggest that at current clinical dosages, plasma concentrations of these drugs may be lower in paediatric than adult patients.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":"3611-3621"},"PeriodicalIF":3.0,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13619026/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148359645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unsupervised machine learning for multi-system adverse event pattern detection in pharmacovigilance: A proof-of-concept analysis of fluoroquinolone reports in FAERS.","authors":"Niaz Chalabianloo, Sheikh S Abdullah, Kamran Sedig, Flory T Muanda","doi":"10.1002/bcp.70853","DOIUrl":"https://doi.org/10.1002/bcp.70853","url":null,"abstract":"<p><strong>Aims: </strong>Traditional pharmacovigilance detects single drug-event associations but cannot readily characterize multi-system adverse-event patterns such as fluoroquinolone-associated disability. We evaluated unsupervised machine learning for this purpose, using fluoroquinolones as an exemplar.</p><p><strong>Methods: </strong>We analysed 40 127 adult fluoroquinolone primary-suspect reports from the FDA Adverse Event Reporting System (FAERS, 2004-2025). Events were encoded as binary MedDRA Preferred Term (PT) and System Organ Class matrices; seriousness and outcome were excluded from clustering and used only post hoc. Multiple correspondence analysis with k-means was primary, validated by k-modes and hierarchical clustering. Cluster number (k = 2-15) was assessed by internal validity indices with bootstrap stability. Comparators were macrolides (n = 39 948) and amoxicillin (n = 16 310).</p><p><strong>Results: </strong>At PT level, silhouette and Calinski-Harabasz indices were optimal at two clusters (Davies-Bouldin at three; silhouette 0.560), separating a multi-system cluster (4072 reports; 10.1%) enriched for neuropsychiatric, musculoskeletal and sensory terms (lifts: memory impairment 8.6, muscle atrophy 8.3, dry eye 7.8). Excluding seriousness and outcome left the cluster essentially unchanged (91.4% retained; κ 0.95), indicating definition by event topology, not case severity; independent algorithms recovered the same subgroup across granularities. Post hoc, the cluster was disproportionately disabling (43.0% vs. 11.7%). The fixed signature classified 14.9% of fluoroquinolone reports vs. 5.3% (macrolides) and 3.9% (amoxicillin).</p><p><strong>Conclusions: </strong>Unsupervised clustering of FAERS data identified, without prior clinical input, a reproducible multi-system adverse-event pattern among fluoroquinolone reports, potentially supporting the feasibility of unsupervised exploratory pattern detection in pharmacovigilance. Given the limitations of spontaneous reporting databases, the findings are strictly hypothesis-generating.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104332","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacoeconomics and outcomes research: Redefining value in the era of therapeutic innovation-Editorial.","authors":"Andrej Belančić, Slobodan Janković, Dinko Vitezić","doi":"10.1002/bcp.70841","DOIUrl":"https://doi.org/10.1002/bcp.70841","url":null,"abstract":"","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149073574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetic profiling of imatinib in relation to CYP3A4 activity in leukaemia patients","authors":"Anna Sofie Buhl Rasmussen,&nbsp;Mathilde Rønne Koch,&nbsp;Cecilie Utke Rank,&nbsp;Christen Lykkegaard Andersen,&nbsp;Allan Weimann,&nbsp;Maria Thastrup,&nbsp;Tianwu Yang,&nbsp;Trine Meldgaard Lund,&nbsp;Ib Jarle Christensen,&nbsp;Flemming Nielsen,&nbsp;Tore Bjerregaard Stage,&nbsp;Sara Bisgaard Jensen,&nbsp;Mette Klarskov Andersen,&nbsp;Kjeld Schmiegelow,&nbsp;Kim Dalhoff","doi":"10.1002/bcp.70622","DOIUrl":"10.1002/bcp.70622","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Imatinib pharmacokinetics exhibit large interindividual variability because of differences in CYP3A4 activity—the main imatinib-metabolizing enzyme. While therapeutic drug monitoring is effective, it requires steady-state conditions and frequent sampling. The endogenous biomarker 4β-hydroxycholesterol (4-β-OHC) has been proposed to reflect CYP3A4 activity, enabling proactive dose optimization. This study investigated 4-β-OHC as a CYP3A4 biomarker in leukaemia patients and its relationship with imatinib pharmacokinetics</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A pharmacokinetic study included 19 patients with chronic myeloid leukaemia or acute lymphoblastic leukaemia receiving imatinib. Blood samples were collected over 24 h. Imatinib, N-desmethyl imatinib, 4-β-OHC and 4α-hydroxycholesterol (4-α-OHC) plasma concentrations were quantified by liquid chromatography–tandem mass spectrometry (LC–MS/MS), while total cholesterol was measured by clinical chemistry autoanalyser. CYP3A4 activity was estimated using the 4-β-OHC/cholesterol ratio. Genotyping of relevant <i>CYP3A4/5</i> gene variants was carried out. Pharmacokinetic parameters were estimated using PKanalix software. Simple and multiple linear regressions were performed</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Nineteen patients were included with median age of 66 years (range 44–77). Pharmacokinetic parameters were comparable to prior reporting. The 4-β-OHC/cholesterol ratio showed a significant positive association with imatinib clearance, explaining 30% of variance. No significant association was found between CYP3A4 activity and N-desmethyl-imatinib area under the concentration time–curve (AUC)/imatinib AUC ratio. Single-point sampling of imatinib at 3–4 h post-dose correlated better with AUC₀_–24h than trough concentrations. CYP3A4/5 genotype assessment was limited by low patient numbers</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This is the first study investigating 4-β-OHC as a biomarker for CYP3A4 activity in imatinib-treated leukaemia patients, demonstrating clinically meaningful associations with imatinib clearance and supporting further development of this personalized therapy approach.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"92 10","pages":"3375-3386"},"PeriodicalIF":3.0,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/bcp.70622","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148052775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"6-Mercaptopurine metabolic profiles and clinical outcomes in TPMT and NUDT15 phenotypes during maintenance therapy for Thai paediatric acute lymphoblastic leukaemia","authors":"Angkana Winaichatsak,&nbsp;Samart Pakakasama,&nbsp;Usanarat Anurathapan,&nbsp;Piti Techavichit,&nbsp;Hansamon Poparn,&nbsp;Darintr Sosothikul,&nbsp;Lalita Sathitsamitphong,&nbsp;Supaporn Wiwattanakul,&nbsp;Piya Rujkijyanont,&nbsp;Apichaya Puangpetch","doi":"10.1002/bcp.70634","DOIUrl":"10.1002/bcp.70634","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>This study aimed to investigate the real-world profiles of 6-mercaptopurine (6-MP) treatment in various TPMT/NUDT15 phenotype groups among paediatric patients with ALL.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We conducted a prospective cohort study of 104 paediatric patients with ALL during the maintenance phase, collecting baseline data and following up monthly for 5 months. Patients were genotyped and classified as normal (NM), intermediate (IM) or poor (PM) metabolizers based on the <i>TPMT</i> and <i>NUDT15</i> genetic variations. Additionally, TPMT activity and metabolite concentrations (6-thioguanine nucleotides; 6-TGN and 6-methylmercaptopurine nucleotides; 6-MMPN) were also quantified.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The patients were categorized into five TPMT/NUDT15 phenotype groups: NM/NM (73.08%), NM/IM (17.31%), NM/PM (1.92%), IM/NM (3.85%) and IM/IM (3.85%). The tolerated 6-MP dose was lowest in the NM/PM group (18 mg/m², IQR = 8–29 mg/m²) and IM/IM group (25 mg/m², IQR = 8–26 mg/m²). The IM/IM had the highest rate of early neutropenia (75%). TPMT activity remained stable throughout the study except in the NM/PM group, which showed significant fluctuations. Patients with NM/PM had the lowest 6-TGN level, and patients with IM/NM showed high 6-TGN levels. Patients with NM/NM and NM/IM exhibited elevated levels of 6-MMPN, which were associated with the occurrence of hepatotoxicity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The <i>TPMT</i> and <i>NUDT15</i> genes influence the side effects of 6-MP medications. Patients who have variations in both genes are at a higher risk of experiencing toxicity. High levels of 6-TGN are associated with <i>TPMT</i> variants, whereas low levels are linked to <i>NUDT15</i> variants. This could facilitate more precise monitoring of toxicity.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"92 10","pages":"3437-3447"},"PeriodicalIF":3.0,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148175159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gabapentinoids-duloxetine combination therapy for chronic pain: A mechanism oriented rational to bridge theoretical knowledge and real life setting","authors":"Stefania Nobili,&nbsp;Maurizio Evangelista,&nbsp;Elena Lucarini,&nbsp;Elena G. Giugliano,&nbsp;Carla Ghelardini,&nbsp;Laura Micheli,&nbsp;Lorenzo Di Cesare Mannelli","doi":"10.1002/bcp.70689","DOIUrl":"10.1002/bcp.70689","url":null,"abstract":"<p>Chronic pain represents a complex debilitating condition that extends beyond the protective function of physiological pain, often persisting as an independent disease entity. Chronic primary and secondary pain syndromes reflect a multifaceted continuum involving nociceptive, neuropathic and nociplastic mechanisms. The maladaptive plasticity of the peripheral and central nervous system (encompassing the ascending and descending pain pathways) sustains hypersensitivity and correlates with comorbid alterations in mood, cognition, sleep and fatigue, underpinned by functional reorganization of brain networks. In this scenario, traditional analgesics frequently demonstrate limited efficacy, while current guidelines recommend antiepileptic agents and antidepressants, particularly gabapentinoids and duloxetine, as first line pharmacological options. This review explores the mechanistic rationale and clinical evidence supporting the combined use of gabapentinoids and duloxetine in chronic pain management. These agents act on distinct yet complementary targets: gabapentinoids reduce excitatory neurotransmission via modulation of calcium channel activity, whereas duloxetine restores descending noradrenergic inhibition and alleviates comorbid symptoms. Clinical trial and meta-analyses highlight their individual efficacy in diabetic peripheral neuropathy, postherpetic neuralgia and fibromyalgia. Among gabapentinoids, pregabalin exhibits a favourable pharmacokinetic profile that allows rapid titration and demonstrates effectiveness against anxiety-related sleep disorders. Importantly, emerging evidence suggests that their combination may offer additional benefit, particularly in patients with residual pain despite monotherapy, though evidence remains limited to small, short-term studies. This review provides proof of concept by bridging theoretical knowledge and real-life clinical settings aiming to develop treatment protocols based on predominant pain mechanisms that can effectively control hypersensitivity and improve quality of life.</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"92 10","pages":"3333-3353"},"PeriodicalIF":3.0,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/bcp.70689","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148583628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characteristics and temporal trends of EU teratological safety signals and information dissemination to healthcare professionals in the Netherlands—A contribution of the ConcePTION project","authors":"Yrea R. J. van Rijt-Weetink,&nbsp;Rosanne E. Huisman,&nbsp;Jan-Peter van Wieringen,&nbsp;H. J. M. J. (Ineke) Crijns,&nbsp;Florence P. A. M. van Hunsel,&nbsp;Anneke L. M. Passier,&nbsp;Sander Borgsteede,&nbsp;A. C. G. (Toine) Egberts,&nbsp;Laura M. Yates,&nbsp;Eugène P. van Puijenbroek","doi":"10.1002/bcp.70615","DOIUrl":"10.1002/bcp.70615","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>Although regulatory responses to safety signals have been studied, pregnancy-specific data and their dissemination to medical professionals remain unclear. This study examined the characteristics and temporal trends of teratological safety signals prompting the European Medicines Agency to implement risk minimization measures. A secondary aim was to investigate how information on these signals, independent of regulatory communication, was disseminated to medical professionals in the Netherlands.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Teratological safety signals from 2002 to 2022 were retrieved from the European Pharmacovigilance Issues Tracking Tool. For each signal, we recorded the dates of market authorization, first spontaneous report, scientific publication, regulatory decision and dissemination through the Teratology Information Service (TIS) and Dutch professional journals. The source of the signal (spontaneous reports, scientific literature or otherwise) was assessed. Time intervals between events were calculated and visualized.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Twenty-four safety signals pertaining to fetal teratogenesis were identified. At the time of regulatory action, medicines had been on the market for a median of 23.9 years (range 3.2–59.3). Cases or studies published in the scientific literature were the origin for most (<i>n</i> = 18, 75%) teratological safety signals. Amendments of the product information was a regulatory action for all signals; eight (33%) also triggered Direct Healthcare Professional Communications. Apart from these regulatory communications, information may have reached healthcare professionals through scientific literature or other channels, sometimes before and sometimes alongside regulatory decisions.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Teratological safety signals are predominantly scientific literature-driven and often arise decades after marketing. Scientific publications and TIS may provide early guidance, frequently preceding regulatory decisions.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"92 10","pages":"3365-3374"},"PeriodicalIF":3.0,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/bcp.70615","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148052714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety, pharmacodynamics and pharmacokinetics of a novel JAK1-selective inhibitor, IN-115314, in healthy participants: A first-in-human study.","authors":"Ki Young Huh, Jaegu Kang, Haerim Jang, Deborah Kang, In-Jin Jang, Seung Hwan Lee","doi":"10.1002/bcp.70847","DOIUrl":"https://doi.org/10.1002/bcp.70847","url":null,"abstract":"<p><strong>Aims: </strong>Selective JAK1 inhibition can control inflammation in immune-mediated diseases with reduced haematological toxicity. IN-115314, a selective JAK1 inhibitor, was evaluated in a first-in-human, randomized, double-blind, placebo-controlled study in healthy participants for safety, pharmacokinetics (PK) and pharmacodynamics (PD).</p><p><strong>Methods: </strong>In six cohorts, participants received IN-115314 or placebo as single oral doses of 2.5 and 10 mg (cohorts 1 and 2) or single and 7-day multiple doses of 25, 50, 100 and 200 mg (cohorts 3-6). JAK1 and JAK2 inhibition was evaluated by changes from baseline in IL-6-induced phosphorylated STAT1 (pSTAT1) and GM-CSF-induced pSTAT5. PD samples were collected up to 24 h post-dose after a single dose and at steady state, whereas blood and urine PK samples for IN-115314 and IN-116118 were collected up to 72 h, with dose-proportionality assessment.</p><p><strong>Results: </strong>Of 55 randomized participants, 54 completed the study. Adverse events occurred in 13 of 44 (29.5%) IN-115314 recipients and 2 of 11 (18.2%) placebo recipients; all were mild, with no serious adverse events. IN-115314 demonstrated significant, dose-dependent JAK1 inhibition, with maximal inhibition (97.5%) at 200 mg. Plasma concentrations and JAK1 inhibition were well described by a sigmoidal I_max model. JAK2 inhibition was minimal, with no relevant changes in absolute neutrophil or reticulocyte counts. IN-115314 was rapidly absorbed and eliminated, with a terminal half-life of 0.57-2.46 h, supra-dose-proportional but time-invariant PKs and minimal accumulation (accumulation ratio 1.12-1.52).</p><p><strong>Conclusions: </strong>IN-115314 was safe, well tolerated and showed rapid, dose-dependent JAK1 inhibition consistent with its PK profile. (ClinicalTrials.gov registration no.: NCT04297865).</p>","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149073622","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Model-informed precision dosing in paediatric intensive care: Bridging the gap between pharmacological optimization and clinical benefit","authors":"Nadir Yalcin","doi":"10.1002/bcp.70702","DOIUrl":"10.1002/bcp.70702","url":null,"abstract":"&lt;p&gt;Model-informed precision dosing (MIPD) is a clinical decision-support approach that individualizes drug therapy by combining patient-specific data, therapeutic drug monitoring, population pharmacokinetic (popPK) models and Bayesian forecasting algorithms, typically implemented through dedicated software platforms or cloud-based systems integrated with electronic health records. MIPD has become a central concept in contemporary clinical pharmacology, particularly for antimicrobial therapy in intensive care unit (ICU). In neonates and children, developmental pharmacokinetics, organ dysfunction and rapidly changing disease trajectories contribute to substantial variability in the pharmacokinetic and pharmacodynamic (PK/PD) profiles of antibiotics, making standard weight-based dosing particularly vulnerable to underexposure or overexposure.&lt;span&gt;&lt;sup&gt;1, 2&lt;/sup&gt;&lt;/span&gt; MIPD seeks to address this limitation by integrating popPK models with Bayesian forecasting approaches. More recently, next-generation strategies combining physiological modelling with artificial intelligence, particularly digital twin frameworks, have begun to redefine this field. The framework developed by Prunella and colleagues, for instance, incorporates not only individual drug exposure but also bacterial adaptation and resistance dynamics, suggesting a shift from static PK/PD targets towards dynamic, evolution-informed dosing strategies.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; However, the growing ability to improve pharmacological target attainment raises a critical translational question: When, and under what conditions, does MIPD improve patient-centred clinical outcomes?&lt;/p&gt;&lt;p&gt;Yet achieving pharmacological targets does not necessarily ensure clinical benefit. The multicentre randomized controlled DOLPHIN trial in critically ill adults demonstrated that MIPD-guided dosing did not significantly improve ICU length of stay or mortality compared with standard dosing strategies.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; These findings indicate that the relationship between exposure optimization and clinical outcomes is not linear and that determinants of treatment success in infectious diseases extend beyond PK targets alone. Realistically, MIPD should be regarded as a tool for improving dosing accuracy and exposure attainment rather than a standalone intervention expected to directly influence complex outcomes such as mortality or ICU length of stay, which are shaped by multiple patient-, pathogen- and treatment-related factors. In paediatric populations, the available evidence remains largely confined to feasibility studies, with a notable lack of high-quality, multicentre trials demonstrating clear clinical benefit.&lt;/p&gt;&lt;p&gt;Early data from Türkiye provide both encouraging and cautionary insights. A prospective feasibility study conducted in one of the largest paediatric hospitals in the country showed that MIPD-guided dose optimization improved model performance and could be integrated into routine clinical w","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"92 10","pages":"3273-3274"},"PeriodicalIF":3.0,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/bcp.70702","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148435155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"‘An apple a day keeps the doctor away’: Revisiting phlorizin and the humble origins of SGLT2 inhibition","authors":"Carolina Gálvez-Montón","doi":"10.1002/bcp.70708","DOIUrl":"10.1002/bcp.70708","url":null,"abstract":"&lt;p&gt;The saying ‘An apple a day keeps the doctor away’ is often cited as a charming piece of folk wisdom rather than a scientifically grounded health recommendation. Yet, its enduring popularity highlights how empirical observations can sometimes foreshadow later scientific discoveries. When examined through the lens of medical history and pharmacology, this proverb offers an interesting opportunity to reflect on how empirical observations may sometimes precede mechanistic understanding. In particular, the discovery of phlorizin from the apple tree and its later role in the development of sodium–glucose cotransporter 2 (SGLT2) inhibitors provides a compelling historical perspective on the origins of modern glucose-lowering therapy.&lt;/p&gt;&lt;p&gt;In 1835, French chemists first isolated phlorizin, a dihydrochalcone glycoside, from the bark of the apple tree (&lt;i&gt;Malus domestica&lt;/i&gt;).&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; At the time, the compound attracted limited clinical interest, largely due to its bitter taste and the absence of a clear therapeutic application. Like many plant-derived compounds described during the 19th century, its physiological relevance remained uncertain.&lt;/p&gt;&lt;p&gt;This changed in 1885, when Joseph von Mering and Oskar Minkowski observed that administration of phlorizin induced pronounced glucosuria in experimental animals, independent of pancreatic damage.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; This finding was remarkable because it demonstrated that urinary glucose excretion could occur independently of diabetes itself, challenging prevailing assumptions about glucose homeostasis. Intriguingly, just 1 year later—around 1886—the proverb ‘An apple a day keeps the doctor away’ appeared in popular literature.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; Although purely coincidental, this temporal coincidence is historically striking and illustrates how nutritional beliefs and pharmacological discoveries may occasionally intersect.&lt;/p&gt;&lt;p&gt;For decades, phlorizin-induced glucosuria remained primarily a physiological observation rather than a therapeutic strategy. Its mechanism of action was gradually elucidated in the mid-20th century, when studies localized its effect to the renal proximal tubule, where glucose reabsorption occurs. Phlorizin was later shown to inhibit sodium-dependent glucose transport across the tubular epithelium.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;The molecular breakthrough came in the 1990s with the identification of SGLT2 as the primary transporter responsible for reabsorbing approximately 90% of filtered glucose in the kidney.&lt;span&gt;&lt;sup&gt;5&lt;/sup&gt;&lt;/span&gt; Although phlorizin itself proved unsuitable for clinical use—owing to poor oral bioavailability, rapid hydrolysis, lack of selectivity and gastrointestinal side effects related to intestinal SGLT1 inhibition—it provided the essential pharmacological template for the development of selective SGLT2 inhibitors.&lt;/p&gt;&lt;p&gt;This ultimately led to the gliflozins, which are now established therapies not only for type 2 diabetes but als","PeriodicalId":9251,"journal":{"name":"British journal of clinical pharmacology","volume":"92 10","pages":"3275-3276"},"PeriodicalIF":3.0,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/bcp.70708","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148444367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}